Hair cells in the inner ear are responsible for sensing sounds, and conditions that kill hair cells because hearing loss. Age-related and noise-induced hearing loss is largely attributable to death of hair cells. Similarly, drugs that damage hearing-ototoxic drugs--often do so by killing hair cells. Despite our awareness that many drugs can damage hearing, a number of ototoxic drugs is still used. These include the aminoglycoside antibiotics. Aminoglycosides are used in this country to treat chronic life threatening conditions, and in underdeveloped countries often for non-life threatening infections. Our lab is identifying ways to block hair cell death during aminoglycoside treatment. Because it is very challenging to study aminoglycoside ototoxicity in the human ear, we use zebrafish. In addition to inner ear hair cells, zebrafish have hair cells on their surface in a sensory system called the lateral line. These lateral line hair cells inform the fish about movements in the surrounding water, and are similar to mammalian inner ear hair cells in many respects. Unlike hair cells of the inner ear however, they are on the surface of the fish, they readily take up drugs and dyes from the surrounding water, and they are easy to observe. Particularly notable to us--they are also sensitive to aminoglycoside exposure. We made a collection of fish that carry mutations, and identified mutant fish in which lateral line hair cells are not damaged by aminoglycosides. These rare fish may reveal targets we can use for therapies to prevent aminoglycoside toxicity in humans. I propose to study one such fish-persephone. The persephone mutant is notable because it is indistinguishable from normal fish, except that its hair cells do not die when exposed to aminoglycosides. We identified the gene that is altered in persephone, and established that it moves chloride and bicarbonate ions across cell membranes. Altering the normal movement of these ions somehow dramatically protects hair cells in persephone. I want to understand why this happens. The work proposed here should reveal whether the hair cells in the persephone mutant are themselves different from wild type fish. It should also reveal events leading to death of hair cells in wild type fish that do not occur in persephone. These studies should provide new insights into ways to block hair cell death during aminoglycoside treatment. Drugs exist that specifically affect the ion movement that is altered in persephone, and understanding why persephone hair cells do not die when exposed to aminoglycosides has promise for future therapies to protect human hair cells. PUBLIC HEALTH RELEVANCE: Death of hair cells of the inner ear is a prevalent cause of hearing damage and loss in the general population. A number of conditions cause hair cell death, including exposure to aminoglycoside antibiotics. This proposal is aimed at understanding what happens to hair cells when they are exposed to these antibiotics, and to identify ways to protect hair cells during treatment with these antibiotics.